- VEGFC antibody therapy drives differentiation of AML. [Journal Article]
- CRCancer Res 2018 Sep 05
- High expression of vascular endothelial growth factor C (VEGFC) predicts adverse prognosis in acute myeloid leukemia (AML). We therefore explored VEGFC targeting efficacy as an AML therapy using a VE...
High expression of vascular endothelial growth factor C (VEGFC) predicts adverse prognosis in acute myeloid leukemia (AML). We therefore explored VEGFC targeting efficacy as an AML therapy using a VEGFC monoclonal antibody. VEGFC antibody therapy enforced myelocytic differentiation of clonal CD34+ AML blasts. Treatment of CD34+ AML blasts with the antibody reduced expansion potential by 30-50% and enhanced differentiation via FOXO3A suppression and inhibition of MAPK/ERK proliferative signals. VEGFC antibody therapy also accelerated leukemia cell differentiation in a systemic humanized AML mouse model. Collectively, these results define a regulatory function of VEGFC in CD34+ AML cell fate decisions via FOXO3A and serve as a new potential differentiation therapy for AML patients.
- A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity. [Journal Article]
- SRSci Rep 2018 Sep 03; 8(1):13159
- The transcription factor MYB plays key roles in hematopoietic cells and has been implicated the development of leukemia. MYB has therefore emerged as an attractive target for drug development. Recent...
The transcription factor MYB plays key roles in hematopoietic cells and has been implicated the development of leukemia. MYB has therefore emerged as an attractive target for drug development. Recent work has suggested that targeting MYB by small-molecule inhibitors is feasible and that inhibition of MYB has potential as a therapeutic approach against acute myeloid leukemia. To facilitate the identification of small-molecule MYB inhibitors we have re-designed and improved a previously established cell-based screening assay and have employed it to screen a natural product library for potential inhibitors. Our work shows that teniposide and etoposide, chemotherapeutic agents causing DNA-damage by inhibiting topoisomerase II, potently inhibit MYB activity and induce degradation of MYB in AML cell lines. MYB inhibition is suppressed by caffeine, suggesting that MYB is inhibited indirectly via DNA-damage signalling. Importantly, ectopic expression of an activated version of MYB in pro-myelocytic NB4 cells diminished the anti-proliferative effects of teniposide, suggesting that podophyllotoxins disrupt the proliferation of leukemia cells not simply by inducing general DNA-damage but that their anti-proliferative effects are boosted by inhibition of MYB. Teniposide and etoposide therefore act like double-edged swords that might be particularly effective to inhibit tumor cells with deregulated MYB.
- Unilateral macular choroidal neovascularization-a rare manifestation in acute myelocytic leukemia: Case report. [Case Reports]
- MMedicine (Baltimore) 2018; 97(16):e0344
- CONCLUSIONS: This is the first report demonstrating that macular CNV could be an ophthalmic side-effect secondary to initiated chemotherapeutic regimens in patients with M3 AML. Intravitreal injection of ranibizumab could be beneficial and safe in treating this CNV.
- Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia. [Journal Article]
- JMJ Med Chem 2018 Feb 22; 61(4):1499-1518
- A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure-activity-relationshi...
A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure-activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical for FLT3 and CDK inhibition. Compound 50 (FN-1501), which possesses potent inhibitory activities against FLT3, CDK2, CDK4, and CDK6 with IC50 values in the nanomolar range, shows antiproliferative activities against MV4-11 cells (IC50: 0.008 μM), which correlates with the suppression of retinoblastoma phosphorylation, FLT3, ERK, AKT, and STAT5 and the onset of apoptosis. Acute-toxicity studies in mice show that compound 50 (LD50: 186 mg/kg) is safer than AT7519 (32 mg/kg). In MV4-11 xenografts in a nude-mouse model, compound 50 can induce tumor regression at the dose of 15 mg/kg, which is more efficient than cytarabine (50 mg/kg). Taken together, these results demonstrate the potential of this unique compound for further development into a drug applied in acute-myeloid-leukemia (AML) therapeutics.
- Pericarditis associated with cytarabine therapy for acute myelocytic leukemia: a case report. [Case Reports]
- EJEur J Clin Pharmacol 2018; 74(2):181-182
- CONCLUSIONS: This case demonstrates that, although pericarditis induced by cytarabine is rare, early recognition of this potentially life-threatening complication and appropriate management will usually result in the patient's recovery.
- Unexpected infant death secondary to a pulmonary infiltration due to acute myelocytic leukaemia. [Case Reports]
- MJMalays J Pathol 2017; 39(2):193-196
- Acute myeloid leukaemia (AML) often presents with non-specific symptoms such as fatigue, anaemia or infection. Pulmonary involvement is uncommon in AML during the course of the disease and is usually...
Acute myeloid leukaemia (AML) often presents with non-specific symptoms such as fatigue, anaemia or infection. Pulmonary involvement is uncommon in AML during the course of the disease and is usually caused by infection, haemorrhage, leukaemic pulmonary infiltrates and leukostasis. Lung localization of AML is very uncommon and potentially life threatening if not diagnosed and treated rapidly. The authors describe the sudden death of an asymptomatic five-month-infant because of a misdiagnosed lung localization of AML. Autopsy examination followed by histopathological studies showed an extensive leukostasis and extramedullary leukaemic infiltrating the lungs. Special stains and immunohistochemical studies revealed findings consistent with acute myelogenous leukaemia. This case suggests that underlying acute leukaemia should be considered as a cause of flu-like symptoms in infants. Medical personnel are urged to be alert to fever, sore throat, weakness and dyspnea that may be characteristic of serious systemic diseases.
- LncRNA H19 regulates ID2 expression through competitive binding to hsa-miR-19a/b in acute myelocytic leukemia. [Journal Article]
- MMMol Med Rep 2017; 16(3):3687-3693
- Acute myelocytic leukemia (AML) is the most common type of acute leukemia. Long non‑coding RNAs (lncRNAs) serve an important role in regulating gene expression through chromatin modification, transcr...
Acute myelocytic leukemia (AML) is the most common type of acute leukemia. Long non‑coding RNAs (lncRNAs) serve an important role in regulating gene expression through chromatin modification, transcription and post‑transcriptional processing. LncRNA H19 was considered as an independent prognostic marker for patients with tumors. The expression of lncRNA H19 was identified to be significantly upregulated in bone marrow samples from patients with AML‑M2. Furthermore, it was demonstrated that the knockdown of lncRNA H19 resulted in increased expression of hsa‑microRNA (miR)‑19a/b and decreased expression of inhibitor of DNA binding 2 (ID2) in AML cells. The knockdown of lncRNA H19 inhibited the proliferation of AML cells in vitro, which could be partially reversed by ID2 overexpression. Furthermore, the results of the bioinformatic analysis revealed potential hsa‑miR‑19a/b‑3p binding sites in lncRNA H19 and ID2. Altogether, the results of the present study suggest that lncRNA H19 regulates the expression of ID2 through competitive binding to hsa‑miR‑19a and hsa‑miR‑19b, which may serve a role in AML cell proliferation.
- Matrine induces Akt/mTOR signalling inhibition-mediated autophagy and apoptosis in acute myeloid leukaemia cells. [Journal Article]
- JCJ Cell Mol Med 2017; 21(6):1171-1181
- Pharmacological modulation of autophagy has been referred to as a promising therapeutic strategy for cancer. Matrine, a main alkaloid extracted from Sophora flavescens Ait, has antitumour activity ag...
Pharmacological modulation of autophagy has been referred to as a promising therapeutic strategy for cancer. Matrine, a main alkaloid extracted from Sophora flavescens Ait, has antitumour activity against acute myelocytic leukaemia (AML). Whether autophagy is involved in antileukaemia activity of matrine remains unobvious. In this study, we demonstrated that matrine inhibited cell viability and colony formation via inducing apoptosis and autophagy in AML cell lines HL-60, THP-1 and C1498 as well as primary AML cells. Matrine promoted caspase-3 and PARP cleavage dose-dependently. Matrine up-regulated the level of LC3-II and down-regulated the level of SQSTM1/p62 in a dose-dependent way, indicating that autophagy should be implicated in anti-AML effect of matrine. Furthermore, the autophagy inhibitor bafilomycin A1 relieved the cytotoxicity of matrine by blocking the autophagic flux, while the autophagy promoter rapamycin enhanced the cytotoxicity of matrine. Additionally, matrine inhibited the phosphorylation of Akt, mTOR and their downstream substrates p70S6K and 4EBP1, which led to the occurrence of autophagy. In vivo study demonstrated that autophagy was involved in antileukaemia effect of matrine in C57BL/6 mice bearing murine AML cell line C1498, and the survival curves showed that mice did benefit from treatment with matrine. Collectively, our findings indicate that matrine exerts antitumour effect through apoptosis and autophagy, and the latter one might be a potential therapeutic strategy for AML.
- Autologous stem cell transplantation for adult acute myelocytic leukemia in first remission-Better outcomes after busulfan and melphalan compared with busulfan and cyclophosphamide: A retrospective study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). [Journal Article]
- CCancer 2017 Mar 01; 123(5):824-831
- CONCLUSIONS: In patients with AML in first complete remission who undergo ASCT, the BUMEL combination is a better preparative regimen. Cancer 2017;123:824-31. © 2016 American Cancer Society.
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- [Comparison of Curative Effects of HAG and CAG Regimens for Patients with AML and Medium/High-Risk MDS]. [Journal Article]
- ZSZhongguo Shi Yan Xue Ye Xue Za Zhi 2016; 24(3):698-701
- CONCLUSIONS: Both CAG and HAG regimens have shown significant curative effects for acute myelocytic leukemia and high/medium-risk myelodysplastic syndrome.